Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

Cunningham, Matthew P.; Thomas, Hilary; Fan, Zhen; Modjtahedi, Helmout

doi:10.1158/0008-5472.can-06-1000

Cited by 35 publications

(40 citation statements)

References 42 publications

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“…Our data show that cetuximab can block EGF binding to its receptor in both sensitive and resistant cell lines, thus reducing ERBB1-phosphorylation, an observation that has been reported previously with anti-ERBB1 antibodies in CRC, head/neck squamous, and nonsmall cell lung cancer cell lines (21,29). EGFinduced downstream ERK1/2 phosphorylation was incompletely abolished by 20 μg/mL of cetuximab in vitro, a concentration, however, that is likely to be much higher than that present in a tumor in a clinical setting.…”

Section: Discussionsupporting

confidence: 87%

“…These data further support the use of a wellcharacterized panel of cell lines to determine clinically relevant molecular markers (16)(17)(18)(19). The large number of cell lines in our panel explains why we have found an association with KRAS in contrast to other CRC cell line studies (20,21). We have also demonstrated that the direct effects of cetuximab are largely replicated with lapatinib, lending support to its potential role as an alternative form of therapy.…”

Section: Discussionsupporting

confidence: 77%

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Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

Ashraf

Nicholls

Wilding

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A significant proportion of colorectal cancer (CRC) patients are resistant to anti-ERBB1 [avian erythroblastic leukemia viral (v-erbb) oncogene homolog, receptor for EGF] monoclonal antibodies (Mabs). We evaluated both immune and nonimmune effects of cetuximab (anti-ERBB1 Mab), trastuzumab (anti-ERBB2 Mab), pertuzumab (anti-ERBB2 Mab), and lapatinib (dual ERBB1 and ERBB2 tyrosine kinase inhibitor) in a large well-characterized panel of 64 CRC cell lines to find response predictive tumor characteristics. There was a significant correlation between the direct effects of cetuximab and lapatinib. Both agents were associated (P = 0.0004) with "triple' wild-type status in KRAS, BRAF, and PIK3CA exon 20. Most cell lines were resistant to the direct effects of anti-ERBB2 Mabs, suggesting that the effects of lapatinib might mainly be through ERBB1. Microarray mRNA expression profiles of sensitive and resistant cell lines showed that although ERBB1 receptor or ligand levels did not associate with cetuximab sensitivity, high levels of ERBB2 (P = 0.036) and amphiregulin (P = 0.026) predicted sensitivity to lapatinib. However, higher ERBB1 expression predicted susceptibility to cetuximab-induced antibody-dependent cellular cytotoxicity and occurred independently of KRAS/BRAF/ PIK3CA mutations (P = 0.69). Lapatinib may be an effective alternative therapy to cetuximab in triple wild-type tumors. Microarray analysis provides suggestive biomarkers for resistance. ERBB1 levels, independent of mutation status, predict immune killing. Therefore, anti-ERBB1 antibodies may be considered in CRC tumors with higher ERBB1 expression and favorable FcγR polymorphisms.anti-ERBB1 therapy | immune-mediated killing | high throughput screening M onoclonal antibodies against the epidermal growth factor receptor, ERBB1 [avian erythroblastic leukemia viral (v-erb-b) oncogene homolog, receptor for EGF], including in particular cetuximab, are now commonly used in colorectal cancer (CRC) treatment (1-3). However, only 20% of patients respond to anti-ERBB1 monotherapy (3). The search for predictive markers to improve clinical outcomes (1, 3) has identified that the presence of a KRAS mutation predicts an adverse response leading to routine KRAS testing before anti-ERBB1 therapy (4). However, KRAS mutations are present in only 30-40% of CRC tumors and a significant proportion of KRAS wildtype (WT) patients (50-65%) do not respond to anti-ERBB1 therapy (3). To improve therapeutic outcomes (5), we therefore need to improve understanding of the roles of different antibodykilling mechanisms and the properties of tumors that determine their response to antibody treatment.The relative contributions of immune [for example antibodydependant cellular cytotoxicity (ADCC) and antibody-dependant cellular phagocytosis (ADCP)] and nonimmune processes (competitive blocking of receptor-ligand binding) to tumor response following antibody therapy are not yet clear (5, 6). The FcγR polymorphism has been shown to be an independent predictor of response to cetuximab in CR...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 77%

Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

Ashraf

Nicholls

Wilding

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…We found that, with the exception of the EGFR overexpressing cell line, DiFi, which was highly sensitive to treatment with both ICR62 and gefitinib, treatment with a combination of ICR62 and gefitinib did not enhance the growth inhibitory effect of the single agent in DiFi cells nor did it sensitize colorectal tumour cells that were insensitive to treatment with the single agent (20). The aim of this study was to evaluate the sensitivity of these colorectal tumour cell lines to treatment with afatinib (BIBW2992), an irreversible erbB family blocker (21-28) currently used in phase III clinical trials, and various cytotoxic drugs.…”

Section: Introductionmentioning

confidence: 80%

“…We have previously investigated the growth response of a panel of human colorectal tumour cell lines to treatment with our anti-EGFR mAb, ICR62, used alone and in combination with the reversible EGFR TKI, gefitinib (20). We found that, with the exception of the EGFR overexpressing cell line, DiFi, which was highly sensitive to treatment with both ICR62 and gefitinib, treatment with a combination of ICR62 and gefitinib did not enhance the growth inhibitory effect of the single agent in DiFi cells nor did it sensitize colorectal tumour cells that were insensitive to treatment with the single agent (20).…”

Section: Introductionmentioning

confidence: 99%

“…The relationship between the expression of EGFR family members and growth inhibition by these agents and their effects on cell cycle distribution were also investigated. (20). All the cell lines were routinely cultured in Dulbecco's modified Eagle's medium (DMEM) (Sigma, UK) supplemented with 10% foetal bovine serum (FBS) (PAA Laboratories, UK) and the antibiotics, penicillin, streptomycin and neomycin, were maintained at 37˚C in a humidified atmosphere with 5% CO 2 .…”

Section: Introductionmentioning

confidence: 99%

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Growth response of human colorectal tumour cell lines to treatment with afatinib (BIBW2992), an irreversible erbB family blocker, and its association with expression of HER family members

Modjtahedi¹

2011

Int J Oncol

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Abstract. Despite the approval of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs), cetuximab and panitumumab, for the treatment of colorectal cancer patients, there is currently no reliable predictive marker for response to therapy. In addition, the duration of response is often limited. Therefore, this study aimed to investigate the effect of afatinib, an irreversible erbB family blocker, as a single agent or in combination with cytotoxic drugs (5-fluorouracil, irinotecan and oxaliplatin) or mAb ICR62 on the proliferation of a panel of human colorectal tumour cell lines and the association between the expression levels of the EGFR family members and response to treatment. Of the cells examined, EGFR-overexpressing DiFi cells were the most sensitive to treatment with both afatinib (IC 50 =45 nM) and ICR62 (IC 50 =4.33 nM). Afatinib also inhibited the growth of other tumour cell lines with IC 50 values which ranged from 0.33 µM (CCL-221) to 1.62 µM (HCT-116). A significant association was found between the co-expression of EGFR, human epidermal growth factor receptor (HER)-2 and HER-3 and response to treatment with afatinib (R=0.915, P=0.021). Treatment with afatinib and cytotoxic drugs was accompanied by an increase in the proportion of these cells in the sub-G0/G1 and in the S and G2/M phase of the cell cycle, respectively. We conclude that afatinib as monotherapy or in combination with other drugs shows activity in colorectal tumour cells and that determination of the co-expression of HER family members should be conducted in clinical trials using drugs targeting erbB signaling. This approach could lead to the identification of a specific subpopulation of cancer patients more likely to benefit from erbB-directed therapy.

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Role of EGFR expression levels in the regulation of integrin function by EGF

Vial

McKeown‐Longo

2015

Molecular Carcinogenesis

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Activation of β1 integrins in dormant tumor cells has been linked to metastatic progression, suggesting that therapies designed to maintain β1 integrins in an inactive state may be useful in the prevention of metastatic disease. Our earlier studies have demonstrated that EGF regulates the activation state of the α5β1 integrin in EGFR overexpressing tumor cells through an ERK/p90RSK signaling pathway. Activation of this pathway by EGF resulted in the Filamin A dependent inactivation of the α5β1 integrin receptor for fibronectin. The current study was designed to address the role of EGFR overexpression in the regulation of α5β1 integrin activation state by EGF. Lentiviral knockdown of EGFR coupled with limited dilution cloning was used to develop A431 squamous carcinoma cell lines expressing high, moderate and low levels of EGFR. Inactivation of α5β1 integrin by EGF was shown to correlate with both the level of EGFR expression and the extent of p90RSK phosphorylation, but not with the level of ERK phosphorylation, suggesting that high levels of EGFR promote α5β1 integrin inactivation through sustained activation of p90RSK. Treatment of cells with EGFR kinase inhibitor resulted in a reactivation of the integrin which could be reversed with the phosphatase inhibitor, Menadione. Taken together, these findings indicate that p90RSK may function to maintain dormancy in tumor cells expressing high levels of EGFR.

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Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

Cited by 35 publications

References 42 publications

Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

Growth response of human colorectal tumour cell lines to treatment with afatinib (BIBW2992), an irreversible erbB family blocker, and its association with expression of HER family members

Role of EGFR expression levels in the regulation of integrin function by EGF

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